Type 2 diabetes is a growing health problem affecting more than 20 million people. Type 2 diabetes is often associated with obesity or with weight gain, although patients with normal weight can also suffer from this disease. The pre-diabetic states of impaired glucose tolerance and/or impaired fasting glucose are common indicators of future development of this disease.
Impaired glucose tolerance is typically defined as two hour glucose levels of 140 to 199 mg/dL (7.8 to 11 mmol) on a 75 g oral glucose tolerance test. The criteria for impaired fasting glucose is typically either of: a fasting plasma glucose level form 6.1 mmol/l (110 mg/dL) to 6.9 mmol/l (125 mg/dL, or a fasting plasma glucose level from 5.6 mmol/L (100 mg/dL) to 6.9 mmol/L (125 mg/dL). Impairments of glucose tolerance persist and often worsen in individuals who progress to develop type 2 diabetes, such that elevated glucose levels in the fed condition are a hallmark of both impaired glucose tolerance and type 2 diabetes.
Treatment modalities typically include lifestyle management such as weight loss, limiting carbohydrate intakes, and regular exercise. Reducing excess weight, in e.g. an overweight patient, can be challenging, however, at least in part because most diet or pharmaceutical interventions result in a regain of most weight once discontinued. For example, most anti-obesity or weight loss medications fail to produce durable weight loss.
MetAP2 encodes a protein that functions at least in part by enzymatically removing the amino terminal methionine residue from certain newly translated proteins such as glyceraldehyde-3-phosphate dehydrogenase (Warder et al. (2008) J Proteome Res 7:4807). Increased expression of the MetAP2 gene has been historically associated with various forms of cancer. Molecules inhibiting the enzymatic activity of MetAP2 have been identified and have been explored for their utility in the treatment of various tumor types (Wang et al. (2003) Cancer Res. 63:7861) and infectious diseases such as microsporidiosis, leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci. 9:34). However, such MetAP2 inhibitors may be useful as well for patients with excess adiposity and conditions related to adiposity including type 2 diabetes, hepatic steatosis, and cardiovascular disease (via e.g. ameliorating insulin resistance, reducing hepatic lipid content, and reducing cardiac workload). Methods of treating overweight subjects that are more effective than e.g. dieting alone are clearly needed, as well as methods of treating patient suffering from diabetes or glucose intolerance.